P1141: ENCOURAGING COMPLETE RESPONSES (CRS) OBSERVED WITH CDK9 INHIBITOR AZD4573 IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) PERIPHERAL T-CELL LYMPHOMA (PTCL): EARLY TRIAL ANALYSIS
Authors: Jake Shortt, Tatyana Feldman, Graham Collins, Jasmine Zain, Amit Khot, Jin Seok Kim, Franck Morschhauser, Tae Min Kim, Justine Roderick, Jeong Lim Yoon, Shringi Sharma, Jamal Saeh, Jiale Dai, Ruben Reyes, Richardp Olsson, Pier Luigi Zinzani
Journal: HemaSphere (2023)

Topic: 19. Aggressive Non-Hodgkin lymphoma - Clinical Background: Patients with r/r PTCL have limited treatment options and poor outcomes to standard of care therapy. CDK9 regulates transcription elongation through phosphorylation of RNA polymerase II. AZD4573 is a highly potent and selective CDK9 inhibitor that downregulates short-lived transcripts and labile proteins such as MCL1, BFL1, and MYC, which are overexpressed in haematologic tumours, including T cell lymphoma. Based on preclinical experiments using T cell lines, and primary PTCL samples, AZD4573 demonstrated in vitro and in vivo activity against T cell lymphoma through caspase activation (Cidado, Clin Cancer Res 2020;26:922–34). In a phase 1, first-in-human study in pts with haematologic malignancies, the recommended phase 2 dose of AZD4573 monotherapy was 12 mg IV QW (Brümmendorf, ASH 2022, abs 1353). Aims: To determine the efficacy and safety of AZD4573 monotherapy in pts with r/r PTCL, in a phase 2a study (NCT05140382). Methods: Pts in this single-arm, open-label study were ≥18 years old, had ECOG PS ≤2, and ≥1 prior line of therapy including an alkylating agent and/or anthracycline. Pts with primary cutaneous or primary leukemic PTCL subtypes were excluded. Each pt received an intra-pt ramp-up of AZD4573: 6 mg on day 1, 9 mg on day 8, then the target dose of 12 mg on day 15, continuing weekly thereafter. The primary objective was efficacy by ORR per investigator assessment (Lugano criteria); secondary objectives included efficacy by complete response rate, duration of response, progression-free survival and overall survival; safety and tolerability; and pharmacokinetics (PK). Results: Eighteen pts received AZD4573; median age was 63.0 years (range 45–83), 66.7% were male and median number of prior regimens was 3.0 (range: 1–9). At the 1 Feb 2023 data cutoff, efficacy was evaluable in 12 pts who had received at least one 12 mg dose. The ORR rate was 3/12 (25.0%, all CRs) in the efficacy-evaluable set (Table). The CRs lasted 7.7 wks to 17.4+ wks. An additional CR was observed in a pt after an initial progressive disease (PD). Safety was evaluable in 18 pts who received ≥1 dose. Treatment-emergent adverse events (TEAEs) occurred in 16 pts (88.9%), all of which were Grade ≥3. Key Grade ≥3 TEAEs were neutropenia (55.6%) and increased aspartate aminotransferase (22.2%). Two pts had TEAEs leading to discontinuation (11.2%; hospitalisation and septic shock, n=1 each). Serious TEAEs were reported in 72.2% and were deemed treatment-related by investigators in 61.1%. Grade 5 treatment-related AEs were reported in 2 pts (11.1%, both septic shock). AZD4573 exhibited linear PK (half-life ~6 hrs) with dose-dependent increases in exposure (Cmax and AUC). Conclusion: Preliminary results show encouraging clinical activity with AZD4573 monotherapy in pts with r/r PTCL, including 3 CRs and one complete metabolic response after initial PD. The PK and safety profiles of AZD4573 monotherapy in PTCL are consistent with the previous phase 1 study with no unexpected findings, and the study continues to expand in the PTCL population.Keywords: Clinical trial, Phase II, relapsed/refractory, Peripheral T-cell lymphoma